AMPARs and NMDAR Diversity Flashcards
Which is faster, NMDARs or AMPARs?
AMPARs, by a lot
What is a property of all AMPARs (that is not subunit dependent)?
High Open probability and rapid activation
What is a property of AMPARs that IS Subunit dependent?
Desensitization recovery (how long it takes before a stimulus depolarizes the channel, different cases for sound or light)
Describe the shared architecture of AMPARs and NMDARs in terms of their domains, polymerity, and shape
Amino Terminal Domain
Ligand Binding Domain
TransMembrane Domain
Homo or heterotetramers with different subgroups that alter pharmacology (two sets of 2 subunits)
Crossing over of 2 proteins between ATD and LBD
What is unique about the GluA2 AMPA Receptor subunit?
They are edited at the Q/R/N site of the M2 loop
Where is the Q/R/N site located in the assembled protein and what is the function?
At the apex of the pore, allows the pore to open/close by twisting open (on a matter of angstroms)
What did Prof Bowie notice about when depolarizing a cell?
Ohm’s law (P = IR) did not apply
meaning something must be offsetting the rectification
What is a property of polyamines?
They can restore rectification
What is the only AMPAR subunit that does not have rectification?
GluA2
How do polyamines block AMPARs?
The Q/R/N site creates a block site that is electronegative, big clunky polyamine hesitates inside and gets stuck
AMPARs preferentially form what type of polymer? What form is favored and which are unstable?
Heteromers
Some homomers are permitted but mostly 2:2 stoichiometry is favored
What are the auxiliary subunits mentioned in class and what do they do?
TARP, Cornichons, CKAMP44, SynDIG1, GSG1L
They bind to AMPA receptors and modify functions
What is an advantage of the heavy regulation of AMPARs?
Different regions of the brain have specific regulation, allowing for drug specificity
What is the role of TARP?
Bus that transports AMPARs to the synapse
How do TARPs and CNIHs regular AMPAR gating behaviour?
Increasing the signalling time through the KGK site of GluA2
What is common for nascent AMPAR RNA?
Alternate splicing and RNA editing
What are the two functional AMPAR families?
GluA2-containing, and -lacking
What are the 3 properties of GluA2-containing AMPARs?
They are Ca2+ impermeable, polyamine-insensitive, and have low unitary conductance
What are the 3 properties of GluA2-lacking AMPARs?
They are Ca2+ permeable, polyamine-sensitive, and have high unitary conductance
True/False? There are many mechanisms designed to relieve AMPAR polyamine block
True
What are the two most important features of NMDA receptors?
High Ca permeability (useful for brain plasticity and maturation)
Gating properties (Mg blocks the pore until it is depolarized, then lets Ca in)
Define the slow gating found in NMDA receptors
A single ms pulse of glutamate will keep the channel open for hundreds of milliseconds
Define the polymerity of NMDA receptors
Obligate tetramers
GluN1, binds glycine
GluN2, binds glutamate
(GluN3 not talked about but binds glycine)
Which NMDA subunit has different types? What is the difference between them?
GluN2 (has 4)
GluN3 (has 2)
Different types of subunit have different pharmacologies
Which heteromer of DNMAR is relatively the fastest to open? Why “relatively”?
GluN1-GluN2A
Relatively because it’s on the order of 100 ms compared to the ~5 ms of an AMPAR
Which heteromer of DMNAR is the slowest to open?
GluN1-GluN2D
opens for ~10s
Which NMDA subunit has the highest Single-Channel conductance? The lowest?
HIghest: 2A and 2B (tied)
Lowest: 2C and 2D (tied)
Which NMDA subunit has the highest open probability? the lowest?
Highest: 2A
Lowest: 2C and 2D (tied)
Why are NMDARs considered “coincidence detectors”?
Only open when the cell is depolarized (relies on Mg2+ block)
Which GluN2 type has an expression profile that overlaps with GluN1?
GluN2A-D
How are NMDARs regulated?
Numerous endogenous modulators
